US4950652A - dsRNAs for combination therapy in the treatment of viral diseases - Google Patents

dsRNAs for combination therapy in the treatment of viral diseases Download PDF

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Publication number
US4950652A
US4950652A US07/125,097 US12509787A US4950652A US 4950652 A US4950652 A US 4950652A US 12509787 A US12509787 A US 12509787A US 4950652 A US4950652 A US 4950652A
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dsrna
rifn
mismatched
hiv
virus
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US07/125,097
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English (en)
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William A. Carter
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Hem Research Inc
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Hem Research Inc
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Priority to US07/125,097 priority Critical patent/US4950652A/en
Assigned to HEM RESEARCH, INC., 12280 WILKINS AVENUE, ROCKVILLE, MARYLAND A CORP. OF MARYLAND reassignment HEM RESEARCH, INC., 12280 WILKINS AVENUE, ROCKVILLE, MARYLAND A CORP. OF MARYLAND ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: CARTER, WILLIAM A.
Priority to ES88301824T priority patent/ES2066782T3/es
Priority to EP88301824A priority patent/EP0286224B1/en
Priority to AT88301824T priority patent/ATE82688T1/de
Priority to DE8888301824T priority patent/DE3876125T2/de
Priority to AU12562/88A priority patent/AU1256288A/en
Priority to PH36590A priority patent/PH23333A/en
Priority to IL85646A priority patent/IL85646A/xx
Priority to NZ223868A priority patent/NZ223868A/xx
Priority to FI881305A priority patent/FI881305A/fi
Priority to NO881246A priority patent/NO881246L/no
Priority to CA000562015A priority patent/CA1316832C/en
Priority to SU884355439A priority patent/RU2016572C1/ru
Priority to KR1019880003033A priority patent/KR960013435B1/ko
Priority to HU881441A priority patent/HUT46542A/hu
Priority to PT87039A priority patent/PT87039B/pt
Priority to JP63065933A priority patent/JP2656938B2/ja
Priority to IE83988A priority patent/IE63823B1/en
Priority to DK156688A priority patent/DK156688A/da
Priority to OA59306A priority patent/OA08724A/xx
Priority to CN88101606A priority patent/CN1049357C/zh
Publication of US4950652A publication Critical patent/US4950652A/en
Application granted granted Critical
Priority to GR920402678T priority patent/GR3006340T3/el
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Expired - Lifetime legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention relates to the use of dsRNA in synergistic combination with other materials that inhibit viral activity or expression to control or in the treatment of viral diseases.
  • Double-stranded RNAs such as poly I.poly C
  • dsRNAs can act as biological response modifiers eliciting antiviral, antineoplastic and immunomodulatory activities.
  • IFN interferon
  • other cytokines as well as activation of certain INF-induced enzymes including 2,5-oligoadenylate synthetase and a ribosome-associated protein kinase.
  • n .r(C 12-14 -U) n (Ampligen) has a low toxicity profile in humans, is active against HIV infection both in vitro and in vivo, and is currently in large-scale, controlled clinical trials of AIDS-related complex (ARC).
  • rIFN-alpha A rIFN-beta Ser 17 and rIFN- y as cytokines
  • azidothymidine and phosphonoformate (foscarnet) as inhibitors of reverse trasncription
  • ribavarin as a putative disrupter of mechanisms governing proper mRNA capping
  • amphotericin B as a lipid-binding molecule with anti-HIV activity
  • castanospermine as an inhibitor of glycoprotein processing (1).
  • One of the drugs, azidothymidine appeared to act synergistically in vitro with mismatched dsRNA as described in earlier application Ser. No. 028,823 filed Mar. 23, 1987, now abandoned.
  • This invention includes the use of synergistic combinations of dsRNAs, notably mismatched dsRNAs, together with a member of a wide range of antiviral compounds in the treatment of viral diseases.
  • the combination is administered to a patient in an amount sufficient to inhibit viral activity, inhibit viral expression, or both.
  • Pharmaceutical compositions containing a dsRNA and another antivirally-active compound are described and the results of this combination demonstrating synergism reported below.
  • Azidothymidine the first drug approved in the United States for the treatment of ARC and AIDS, is extremely toxic. This in vivo toxicity is manifested by approximately 30% of patients receiving azidothymidine requiring blood transfusions.
  • the results of my present experiments suggest that drugs like azidothymidine with high in vivo toxicity can be given at substantially lower, less toxic doses if combined with mismatched dsRNA.
  • Combination therapy may not only reduce the effective dose of a drug required for antiviral activity, thereby reducing its toxicity, but may also improve the absolute antiviral effect as a result of attacking the virus through multiple mechanisms.
  • dsRNA in general, and mismatched dsRNA in particular will be an effective core drug for combination therapy yielding the most effective and least toxic treatment for ARC and AIDS.
  • dsRNAs notably mismatched dsRNAs
  • dsRNAs provide a synergistic complement to antiviral therapy in general, and in the treatment of aids-related complex and AIDS itself specifically.
  • dsRNAs when administered in combination with other antiviral drugs known to cause significant toxicity when administered alone and in quantities effective to address the viral condition, have the additional benefit of permitting the clinician to reduce the amount of the toxic member of the combination without adverse affect on the desired therapeutic results of the treatment.
  • mismatched double-stranded RNA (Ampligen®, a registered trademark of HEM Research, Inc. of Rockville, Maryland, USA) as a core drug were performed to identify other agents and mechanisms through which mismatched dsRNA may potentiate effective therapeutic intervention in human immunodeficiency virus (HIV) infection.
  • Antiviral activities were defined by a microtiter infection assay utilizing MT-2 cells as targets and HTLV-III B produced in H9 cells as a virus source.
  • agents tested included rIFN-alpha A, rIFN-beta SER 17, and rIFN- y as cytokines; azidothymidine and phosphonoformate (Foscarnet) as inhibitores of reverse transcription; ribavirin as a putative inhibitor of proper HIV mRNA capping; amphotericin B as a lipophile; and castanospermine as a glycoprotein processing (glucosidase I) inhibitor.
  • each drug demonstrated dose-dependent anti-HIV activity and, when used in combination with mismatched dsRNA, demonstrated synergism.
  • dsRNA was synergistic with all three IFNs for anti-HIV activity in microtiter infection assays, it did not potentiate IFN-induced inhibition of virus production in cultures of H9/HTLV-III B cells.
  • the results of these studies suggest that the pleiotropic activities of dsRNAs differ from those of IFN and may provide synergism in combination therapy with a wide range of antiviral drugs for the treatment of acquired immunodeficiency syndrome (AIDS).
  • AIDS acquired immunodeficiency syndrome
  • the procedures and therapeutic compositions of this invention are intended to include the above-listed agents, as exemplary and illustrative of various classes there named. Various other agents yet to be discovered but synergistic when combination with dsRNAs are also included within the scope of this invention.
  • mismatched dsRNAs are meant those in which hydrogen bonding (base stacking) between the counterpart strands is relatively intact, i.e., is interrupted on average less than one base pair in every 29 consecutive base residues.
  • the term “mismatched dsRNA” should be understood accordingly.
  • the dsRNA may be a complex of polyinosinate and a polycytidylate containing a proportion of uracil bases or guanidine bases, e.g., from 1 in 5 to 1 in 30 such bases (poly I. poly (C 4-29 ⁇ >U or G).
  • the dsRNA may be of the general formula rI n .(C 12 U) n .
  • Other suitable examples of dsRNA are discusses below.
  • the mismatched dsRNAs preferred for use in the present invention are based on copolynucleotides selected from poly (C n ,G) in which n is an integer having a value of from 4 to 29, and are mismatched analogs of complexes of polyriboinosinic and polyribocytydilic acids, formed by modifying rI n .rC n to incorporate unpaired bases (uracil or guanidine) along the polyribocytidylate (rC n ) strand.
  • the dsRNA may be derived from poly (I).
  • poly (C) dsRNA by modifying the ribosyl backbone of polyriboinosinic acid (rI n ) e.g., by including 2'-0-methyl ribosyl residues.
  • rI n polyriboinosinic acid
  • rI n polyriboinosinic acid
  • These mismatched analogs of rI n .rC n preferred ones of which are of the general formula rI n .r(C 11-14 ,U) n and rI n .r(C 29 ,G) n , are described by Carter and Ts'o in U.S. Pat. Nos. 4,130,641 and 4,024,222 the disclosures of which are hereby incorporated by reference.
  • the dsRNAs described therein generally are suitable for use according to the present invention.
  • interferon alpha
  • an amount of from 0.01 to 100,000 IRU per milliliter of the patient's body fluid is provided.
  • dsRNA administered provide a level of from 0.1 to 1,000 micrograms dsRNA per milliliter of the patient's body fluid.
  • body fluid is intended to refer to that solution of serum, salts, vitamins, etc., which circulates within the organism and bathes the tissues.
  • agents a dsRNA and another antiviral compound
  • both agents may be administered as a mixture, administered separately but simultaneously, or sequentially.
  • the complementary antiviral used with the dsRNA is administered in quantities consistent with the product labeling or other directions for use and often in somewhat smaller amounts due to the concurrent use of the dsRNA and the synergistic result of the combination.
  • Administration of a dsRNA and another antiviral agent "in combination” includes presentations in which both agents are administered together as a therapeutic mixture, and also procedures in which the two agents are administered separately but simultaneously, e.g., as through separate intravenous lines into the same individual.
  • Administration "in combination” further includes the separate administration of one of the drugs in which one of the drugs is given first followed shortly by the second.
  • HTLV-I-transformed T-cell line MT-2 which exhibits complete cytolysis upon infection with HIV(19) was used as the target for infections in microtiter assays.
  • Virus was prepared from H9/HTLV-III B culture fluids by low speed centrifugation and 0.45 ⁇ M filtration to remove all cells.
  • Viral titers were determined from 50% tissue culture infectious dose (TCID-50) values obtained by endpoint microtitration on MT-2 cells. All cultures were grown and maintained in RPMI-1640 containing 16% heat-inactivated fetal calf serum and 50 ⁇ g gentamicin (Sigma)/ml.
  • Antivirals--Human rIFN- ⁇ A >10 8 IU/mg
  • rIFN- y 1. ⁇ 10 8 IU/mg
  • azidothymidine was obtained from Hoffman-La-Roche.
  • Human rIFN- ⁇ .Ser 17 1.0 ⁇ 10 8 IU/mg
  • IFNs were calibrated in WISH cells challenged with vesicular stomatitis virus and assayed for cytopathic effect as previously described (2).
  • Reference standards were obtained from the World Health Organization (human IFN- ⁇ , WHO standard B,69/19 and human IFN- ⁇ , WHO no.
  • Amphotericin B (Fungizone) was obtained from GIBCO, castanospermine from Boehringer Mannheim, ribavirin (Virazole) from Viratel. Inc., and phosphonoformate (Foscarnet) from Astra Alab AB. Mismatched dsRNA (Ampligen) was provided as a lyophilized powder in a salt buffer by HEM Research, Inc., Rockville, Maryland.
  • Microtiter Infection Assay--Anti-HIV activities were measured in a microtiter infection assay as described (2). Briefly, two-fold, serial dilutions of each drug alone and in fixed-ratio combination with mismatched dsRNA were assayed in triplicate in 96-well microtiter plates. Cytolysis was measured via vital dye (neutral red) uptake by poly-L-lysine adherent cells as an endpoint for infection. Cells were incubated in the presence of drug dilutions for 1 hour prior to addition of virus. In the case of amphotericin B, both virus and cells were preincubated with drug prior to challenge.
  • vital dye neutral red
  • fa is the fraction affected by dose D
  • fu is the unaffected fraction
  • Dm is the dose required for 50% effect
  • m is the slope of the dose-effect curve.
  • mutually exclusive drugs i.e., similar mode of action
  • both drugs alone and their mixture give parallel lines in the median effect plot.
  • mutually nonexclusive drugs i.e., independent mode of action
  • ⁇ is 0, and if they are mutually nonexclusive, ⁇ is 1.
  • Values obtained assuming mutual nonexclusiveness will always be slightly greater than mutually exclusive drugs.
  • Cl values of ⁇ 1 indicate synergy, values >1 indicate antagonism and values equal to 1 indicate additive effects.
  • Our data was analyzed with the assistance of an IBM-PC-compatible computer program.
  • Antiviral Activities The ability of each drug alone and in combination with mismatched dsRNA to protect target cells from HIV infection is shown in Table 1. With the exception of ribavirin, full protection was observed at all concentrations of each drug early in the incubation period immediately following cytolysis in the virus control (no effectors) wells. Virus-induced cytolysis at the lower doses of these drugs occurred one day later and assays were processed again at this time so that dose-dependent relationships could be achieved. Assays were also processed for ribavirin at this time, although full protection was never achieved at any sub-toxic concentration of this drug, even early in the infection process. The most effective (>10% protection) concentrations of each drug produced greater anti-HIV activity in combination with mismatched dsRNA than when used alone. All drugs were non-toxic to MT-2 cells at the concentrations utilized in these studies.
  • Virus Synthesis--virus production in H9/HTLV-III B cultures was examined in the presence and absence of IFNs, mismatched dsRNA and the combination of these drugs (Table 3). Mismatched dsRNA alone (50 ⁇ g/ml) had very little effect on the virus production (6% decrease) while rIFN- ⁇ A, rIFN- ⁇ , and rIFN- y (500 IU/ml) inhibited virus production by 53%, 56%, and 20%, respectively.
  • mismatched dsRNA resulted in a mild reduction, in the inhibition of virus production induced by the IFNs, where this inhibition was decreased from 53% to 47% for rINF- ⁇ A, from 56% to 51% rIFN- ⁇ , and from 20% to 15% for rINF- y .
  • Other studies indicate these concentrations of mismatched dsRNA and rIFNs alone or in combination had no effect on cell division.
  • mismatched dsRNA may have a powerful and versatile role as a core drug in combination therapy for ARC and AIDS.
  • Double-stranded RNAs, including mismatched dsRNA activate IFN-induced enzymes involved in the establishment of an antiviral state, including 2,5-oligoadenylate synthetase and a ribosome-associated protein kinase.
  • Another class of anti-HIV drugs the inhibitors of reverse transcription, I have also found to be synergistic with mismatched dsRNA.
  • the two inhibitors used in this study were azidothymidine and foscarnet.
  • Azidothymidine a thymidine analog, becomes phophorylated intracellularly and is incorporated into nascent DNA where it causes premature chain termination.
  • Phosphorylated azidothymidine is utilized by reverse transcriptase 100 times more effectively than by cellular DNA polymerases, thus allowing a seemingly large window of selectivity.
  • Phosphonoformate (Foscarnet) another inhibitor of reverse transcription, has strong anti-HIV activity in vitro in addition to selectively inhibiting influenza virus RNA polymerase and herpes virus DNA polymerase. Both of these drugs demonstrated potent, selective inhibition of HIV in the microtiter infection assay; see Table 1. Their observed synergism with mismatched dsRNA (see Table 2) suggests that such synergism may also be observed with other inhibitors of reverse transcription.
  • Ribavirin may represent a class of anti-HIV drugs which interfere with 5'-mRNA processing. Although the mechanism of antiviral activity of ribavirin is not clear, this drug is thought to compete with quanosine in the formation of mRNA cap structures and/or interfere with the functional methylation of these molecules. Other inhibitors of functional HIV mRNAs, such as antisense DNAs, should also exhibit synergy of this anti-HIV mechanism with mismatched dsRNA.
  • Amphotericin B a polyene macrolide antifungal antibiotic which interacts with sterols and binds to them irreversibly, represents yet another unique class of agents that are active against a variety of lipid-enveloped viruses, including HIV. Although amphotericin B exhibits severe in vivo toxicities, the methyl ester form of this drug also exhibits anti-HIV activity and has a low cellular toxicity profile in vitro. Therefore, amphotericin B methyl ester will be more beneficial in combination therapy with mismatched dsRNA than the parent compound.
  • Castanospermine is a plant alkaloid which inhibits glycoprotein processing, and was investigated because of the envelope of HIV contains two heavily glycosylated proteins, gp120 as an outer membrane glycoprotein and gp41 as a transmembrane glycoprotein. Interaction between gp120 and the OKT4 surface antigen of T cells, which acts as receptor for the virus, is partly responsible for the cellular tropism of HIV. Recent studies by others with glycolases and lectins have shown that protein glycosylation plays an important role in gp120-LKT4 interaction and HIV infection.
  • Maturation of glycoproteins is dependent on a series of enzymes for the processing of carbohydrate moieties which usually results in the transformation of high-mannose to complex-type oligasaccharides.
  • Castanospermine inhibits glucosidase I which results in a high-mannose type N-glycosylated protein.
  • the infectivity of HIV was attenuated (see Table 1).
  • AMPLIGEN® is a registered trademark of HEM Research, Inc., Rockville, MD, USA.

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US07/125,097 1987-03-23 1987-11-25 dsRNAs for combination therapy in the treatment of viral diseases Expired - Lifetime US4950652A (en)

Priority Applications (22)

Application Number Priority Date Filing Date Title
US07/125,097 US4950652A (en) 1987-03-23 1987-11-25 dsRNAs for combination therapy in the treatment of viral diseases
DE8888301824T DE3876125T2 (de) 1987-03-23 1988-03-02 Behandlung der menschlichen viralinfektion durch doppelstrang-rna, kombiniert mit viralen inhibitoren.
EP88301824A EP0286224B1 (en) 1987-03-23 1988-03-02 Treatment of human viral infection by dsrna combined with viral inhibitors
AT88301824T ATE82688T1 (de) 1987-03-23 1988-03-02 Behandlung der menschlichen viralinfektion durch doppelstrang-rna, kombiniert mit viralen inhibitoren.
ES88301824T ES2066782T3 (es) 1987-03-23 1988-03-02 Tratamiento de infecciones virales humanas mediante arn bicatenario combinado con inhibidores virales.
AU12562/88A AU1256288A (en) 1987-03-23 1988-03-02 Treatment of human viral infections by dsrna combined with viral inhibitors
PH36590A PH23333A (en) 1987-03-23 1988-03-03 Treatment of human viral infections by dsrna combined with viral inhibitors
IL85646A IL85646A (en) 1987-03-23 1988-03-07 Therapeutic composition for the treatment of retroviral infections comprising a retroviral compound and a mismatched dsrna
NZ223868A NZ223868A (en) 1987-03-23 1988-03-11 Synergistic treatment of viral infections by dsrna combined with viral inhibitors
FI881305A FI881305A (fi) 1987-03-23 1988-03-18 Behandling av maenniskans virusinfektioner med en kombination av dsrna och virusinhibitorer.
NO881246A NO881246L (no) 1987-03-23 1988-03-21 Fremgangsmaate for fremstilling av terapeutisk preparat inneholdende dsrna og virusinhibitor.
CA000562015A CA1316832C (en) 1987-03-23 1988-03-21 Treatment of human viral infection by dsrna combined with viral inhibitors
SU884355439A RU2016572C1 (ru) 1987-03-23 1988-03-22 Композиция для лечения спида
KR1019880003033A KR960013435B1 (ko) 1987-03-23 1988-03-22 바이러스 억제제 및 dsRNA를 함유하는 바이러스 감염질환 및 HIV 감염질환 치료용 조성물
HU881441A HUT46542A (en) 1987-03-23 1988-03-22 Process for production of medical preparatives containing bifilar rns and virus-inhibitors applicable for human treatment of virus infection
PT87039A PT87039B (pt) 1987-03-23 1988-03-22 Processo para a preparacao de uma composicao farmaceutica para tratamento de infeccoes virais humanas
JP63065933A JP2656938B2 (ja) 1987-03-23 1988-03-22 ｄｓＲＮＡと逆転写酵素インヒビターを含んで成るＨＩＶ感染治療のための医薬組成物
IE83988A IE63823B1 (en) 1987-03-23 1988-03-22 Treatment of human viral infections by dsRNA combined with viral inhibitors
DK156688A DK156688A (da) 1987-03-23 1988-03-22 Praeparat til behandling af virusinfektioner
OA59306A OA08724A (fr) 1987-03-23 1988-03-23 Treatment of human viral infections by dsRNA combined with viral inhibitors.
CN88101606A CN1049357C (zh) 1987-03-23 1988-03-23 利用双链核糖核酸与病毒抑制剂联合以治疗人的病毒感染
GR920402678T GR3006340T3 (pt) 1987-03-23 1992-11-26

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US2882387A 1987-03-23 1987-03-23
US07/125,097 US4950652A (en) 1987-03-23 1987-11-25 dsRNAs for combination therapy in the treatment of viral diseases

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EP (1) EP0286224B1 (pt)
JP (1) JP2656938B2 (pt)
KR (1) KR960013435B1 (pt)
CN (1) CN1049357C (pt)
AU (1) AU1256288A (pt)
CA (1) CA1316832C (pt)
DE (1) DE3876125T2 (pt)
DK (1) DK156688A (pt)
ES (1) ES2066782T3 (pt)
FI (1) FI881305A (pt)
GR (1) GR3006340T3 (pt)
HU (1) HUT46542A (pt)
IE (1) IE63823B1 (pt)
IL (1) IL85646A (pt)
NO (1) NO881246L (pt)
NZ (1) NZ223868A (pt)
OA (1) OA08724A (pt)
PH (1) PH23333A (pt)
PT (1) PT87039B (pt)
RU (1) RU2016572C1 (pt)

Cited By (28)

* Cited by examiner, † Cited by third party
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US5091374A (en) * 1987-07-17 1992-02-25 Hem Research Inc. Double-stranded RNA correction of abnormalities in circulating immune complexes and monocyte function
US5132292A (en) * 1990-05-25 1992-07-21 Hem Research, Inc. Treatment of viral hepatitis
WO1996040191A1 (en) 1995-06-07 1996-12-19 Trimeris, Inc. The treatment of hiv and other viral infections using combinatory therapy
US5614504A (en) * 1990-08-01 1997-03-25 The University Of South Florida Method of making inosine monophosphate derivatives and immunopotentiating uses thereof
US5712257A (en) * 1987-08-12 1998-01-27 Hem Research, Inc. Topically active compositions of mismatched dsRNAs
US5756477A (en) * 1991-04-16 1998-05-26 Societe De Conseils De Recherches Et D'applications Scientifiques Treatment of aids with complex of poly (A). poly (U)
WO1998030223A1 (en) * 1997-01-17 1998-07-16 Icn Pharmaceuticals, Inc. Cytokine related treatments of disease
US5906980A (en) * 1987-07-17 1999-05-25 Hem Research Inc. Treatment of hepatitis with mismatched dsRNA
US6130206A (en) * 1980-07-07 2000-10-10 Hem Research, Inc. Treating viral infections associated with chronic fatigue with dsRNA
DE10100588A1 (de) * 2001-01-09 2002-07-18 Ribopharma Ag Verfahren zur Hemmung der Expression eines Zielgens
US20030051263A1 (en) * 1997-12-23 2003-03-13 The Carnegie Institution Of Washington Genetic inhibition by double-stranded RNA
WO2003051301A2 (en) * 2001-12-14 2003-06-26 Hemispherx Biopharma USE OF dsRNAs IN STRATEGIC THERAPEUTIC INTERVENTION OF HIGHLY ACTIVE ANTIRETROVIRAL THERAPY
US20040002465A1 (en) * 1998-04-07 2004-01-01 Universite Pierre Et Marie Curie Polyene macrolide derivatives, use for vectoring molecules
US20050113292A1 (en) * 2003-07-18 2005-05-26 Vanderbilt University Compositions of protein mimetics and methods of using same against HIV-1, SARS-coV and the like
US20060035859A1 (en) * 2003-05-16 2006-02-16 Hemispherx Biopharma Treating severe and acute viral infections
US20060240410A1 (en) * 1994-06-03 2006-10-26 G.D. Searle & Co. Retroviral protease inhibitor combinations
US20070088077A1 (en) * 1991-02-26 2007-04-19 Plasse Terry F Appetite stimulation and reduction of weight loss in patients suffering from symptomatic hiv infection
US20070141080A1 (en) * 2003-05-16 2007-06-21 Hemispherx Biopharma Treating severe acute respiratory syndrome
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NO881246D0 (no) 1988-03-21
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DK156688D0 (da) 1988-03-22
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OA08724A (fr) 1989-03-31
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CA1316832C (en) 1993-04-27
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IL85646A (en) 1993-05-13
DE3876125T2 (de) 1993-06-09
NO881246L (no) 1988-09-26
CN88101606A (zh) 1988-12-28
NZ223868A (en) 1991-02-26
RU2016572C1 (ru) 1994-07-30
PH23333A (en) 1989-07-14
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PT87039B (pt) 1992-11-30
GR3006340T3 (pt) 1993-06-21

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